Project Summary To continue to march towards developing an effective cure for ALS, it is imperative to: 1) ascertain the contribution of neurons, other than motor neurons, to the disease: 2) identify the molecular mechanisms that trigger or fail to stop pathophysiological changes in neurons, including motor neurons; and 3) develop culture assays that faithfully and reliably recapitulate pathogenic cellular and molecular changes that occur in vivo. In published findings, we and others have shown that sensory axons and nerve endings in the periphery degenerate early and progressively in SOD1G93A and TDP43A315T mice. These cellular features are also found in motor neurons afflicted with ALS, suggesting that the same molecular mechanisms critical for maintaining and repairing axons and their nerve endings may become dysfunctional in both types of neurons. However, the soma of sensory neurons does not atrophy in mice harboring ALS-causing mutant genes despite the degeneration of their nerve endings, indicating that there are differences in how these two neuronal populations respond to ALS-induced pathogenesis. These similarities and differences between sensory and motor neurons affected with ALS present unique opportunities to uncover shared mechanisms involved in axonal degeneration and activated to maintain the viability of the neuronal soma. In this proposal, we will examine the impact of two ALS-causing mutant genes on sensory neurons in vivo and in culture. In aim 1, we will determine cellular changes altered in sensory neurons expressing ALS-causing mutant genes maintained in culture for weeks. In aim 2, we will test the hypothesis that sensory neurons harboring ALS-causing mutant genes are sensitive to cellular stressors, an experiment designed to recapitulate stressors these and other neurons encounter in vivo. In aim 3, we will determine molecular features shared between sensory neurons expressing different ALS-causing mutant genes. Altogether, this proposal will further our understanding of pathological changes that occur in sensory neurons harboring ALS-causing mutant genes, establish primary sensory neurons as a cellular assay in culture to identify and test therapeutics for ALS and uncover molecular mechanisms altered by expression of both, SOD1G93A and TDP43A315T.